The goal of this proposal is to investigate the mechanisms of very long chain fatty acid (VLCFA; >C22:0) induced neuroinflammatory demyelinating disease and to evaluate the efficacy of interventions of these signaling pathways as possible therapeutics for X-Adrenoleukodystrophy (X-ALD). X-ALD, the most common inherited peroxisomal disorder, is caused by pathognomonic accumulation of VLCFA as a result of peroxisomal dysfunction leading to loss of oligodendrocytes and myelin and a shortened life expectancy. The complexities in the transition of inherited metabolic disease into neuroinflammatory disease of X-ALD have frustrated the efforts of various laboratories including ours, to establish the relationship between VLCFA accumulation and induction of the neuroinflammation. By using a comprehensive approach including proteomics and lipidomics on cells (fibroblasts) and autopsy brain from X-ALD and brain cells (astrocytes and oligodendrocytes) from control and X-ALD mice, we have investigated the molecular events associated with the development of neuroinflammatory disease in X-ALD, establishing for the first time, that excessive accumulation of VLCFA induces cellular signaling for inflammatory response in astrocytes and excessive accumulation of VLCFA in the presence of inflammatory mediators induces cellular signaling for apoptotic loss of oligodendrocytes. Based on these observations, we hypothesize that pathognomonic accumulation of VLCFA, as a constituent of different lipids (sphingomyelin/ceramide/lactosylceramide), induces differential signal transduction pathways for sustained inflammatory response in astrocytes and signals for apoptotic loss of oligodendrocytes in X-ALD. The proposed studies are: Specific Aim 1: To elucidate the mechanisms of VLCFA-induced inflammatory response in astrocytes in the X-ALD setting. Specific Aim 2: To elucidate the mechanisms of VLCFA-induced cell death of oligodendrocytes in the setting of X-ALD disease. Specific Aim 3: To evaluate the therapeutic efficacy of compounds (as therapeutics) that attenuate VLCFA derangement induced pathways in astrocytes and oligodendrocytes. The studies on the differential role of VLCFA containing lipids in astrocytes vs. oligodendrocytes are innovative. Understanding the mechanisms of VLCFA-induced inflammatory response in astrocytes and cell death in oligodendrocytes is critical for the development of effective therapy for X-ALD. PUBLIC HEALTH RELEVANCE: X-ALD, the most common genetic disorder of peroxisomes, affects boys in early childhood due to the pathognomonic accumulation of VLCFA. It is also known as Lorenzo's disease based on a movie called Lorenzo's Oil depicting the life of a child suffering from X-ALD. The mutation in ALD gene results in metabolic disease as excessive accumulation of VLCFA, which subsequently leads to neuroinflammatory disease, loss of oligodendrocytes/myelin and a shortened life span. Unfortunately, there is no effective therapy to control neurological disease. Children with X-ALD die within 1-3 years of onset of the neurological disease. The proposed studies are designed to delineate the molecular mechanisms of VLCFA derangement induced signaling that induces the inflammatory response in astrocytes and cell death in oligodendrocytes. Understanding these mechanisms is critical for the development of effective therapy for X-ALD.